Targeting Cancer‐Associated Fibroblasts: Eliminate or Reprogram?

ABSTRACT Cancer‐associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in tumor progression and treatment resistance, CAFs are promising therapeutic targets in cancer. The elimination of tumor‐promoting CAFs has been investigated in various animal models to determine whether it effectively suppresses tumor growth. Based on recent evidence, several simple strategies have been proposed to eliminate tumor‐promoting CAFs and attenuate these features. In addition, attention has focused on the critical role that CAFs play in the immunosuppressive TME. Therefore, the functional reprogramming of CAFs in combination with immune checkpoint inhibitors has also been investigated as a possible therapeutic approach. However, although potential targets in CAFs have been widely characterized, the plasticity and heterogeneity of CAFs complicate the understanding of their properties and present difficulties for clinical application. Moreover, the identification of tumor‐suppressive CAFs highlights the necessity for the development of therapeutic approaches that can distinguish and switch between tumor‐promoting and tumor‐suppressive CAFs in an appropriate manner. In this review, we introduce the origins and diversity of CAFs, their role in cancer, and current therapeutic strategies aimed at targeting CAFs, including ongoing clinical evaluations.